KR20060057569A - Spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin-2'-one] derivative having affinity with alpha 7 nicotinic acetylcholine receptor - Google Patents

Abstract

<Formula I>

Compounds of Formula I and their pharmaceutically acceptable salts, wherein Ar ¹ , A and Ar ² are as defined herein, pharmaceutical compositions and formulations containing them, alone or in combination with other therapeutically active compounds or substances Methods of using them to treat diseases and conditions in combination, processes and intermediates used to prepare them, their use as drugs for treatment, their use in drug manufacture and their use for diagnostic and analytical purposes do.

Description

Spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin-2'-one] derivative having affinity with alpha7 nicotinic acetylcholine receptor {SPIRO [1-AZABICYCLO [2.2.2 ] OCTAN-3,5'-OXAZOLIDIN-2'-ONE] DERIVATIVES WITH AFFINITY TO THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR}

The present invention relates to novel spiroazabicyclic compounds or pharmaceutically acceptable salts thereof, methods for their preparation, pharmaceutical compositions containing them and their use in therapy.

Binding to nicotinic acetylcholine receptors for the treatment of a wide range of disorders involving reduced cholinergic action such as Alzheimer's disease, cognitive impairment, attention disorders, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesic, Tourette's syndrome and Parkinson's disease The use of a compound is described by McDonald et al., (1995) "Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology", Chapter 5 in Annual Reports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc., San Diego, CA; Williams et al., (1994) "Neuronal Nicotinic Acetylcholine Receptors," Drug News & Perspectives, vol. 7, pp. 205-223; Holladay et al. (1997) J. Med. Chem. 40 (26), 4169-4194; Arneric and Brioni (Eds.) (1998) "Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities", John Wiley & Sons, New York; Levin (Ed.) (2001) "Nicotinic Receptors in the Nervous System" CRC Press.

Summary of the Invention

The present invention includes nicotine-based acetylcholine receptor-reactive compounds which are ligands for nicotine-based acetylcholine receptors according to formula (I), ie compounds of the invention (nAChRs) according to formula (I) and their pharmaceutically acceptable salts.

Wherein Q is a residue of formula (II)

-A- is selected from -O-, -S- or -NR ¹ -or is a bond directly connecting Ar ¹ and Ar ² ,

Ar ^l is selected from Formula III or Formula IV,

B is O, S or NR ¹ ,

R ¹ in each occurrence is independently selected from hydrogen or R ³ ,

D is each independently selected from N or CR ² , provided that D is N in two cases or less,

R ² independently in each occurrence is hydrogen, -R ³ , -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, halogen, -CN, -NO ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , -OR ⁸ , Q or a bond, provided that R ² is in one case Q, and in one case is a bond connecting Ar ^l to A or -A- If a bond, it is a bond to Ar ² ,

R ³ is selected from an unsubstituted straight, branched or cyclic C ₁ -C ₆ alkyl group, or up to 5 halogen atoms, and C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -CN, From straight, branched or cyclic C ₁ -C ₆ alkyl groups substituted with up to 2 substituents selected from -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ or -OR ⁸ Selected,

R ⁴ in each occurrence is independently selected from hydrogen, R ⁹ , —NR ¹⁰ R ¹¹ or —OR ⁸ ,

R ⁵ in each occurrence is independently selected from hydrogen, R ⁹ or —NR ¹⁰ R ¹¹ ,

R ⁶ and R ⁷ are each independently selected from hydrogen, R ⁹ , —C (O) R ⁴ or —S (O) _n R ⁵ , or in any case of —NR ⁶ R ⁷ in combination ( CH ₂ ) _p G (CH ₂ ) _q , where G is O, S, NR ^8, or a bond,

R ⁸ is selected from hydrogen or R ⁹ ,

R ⁹ is selected from an unsubstituted straight, branched or cyclic C ₁ -C ₆ alkyl group, or up to 5 halogen atoms, and C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -CN, Is selected from a straight, branched or cyclic C ₁ -C ₆ alkyl group substituted with up to one substituent selected from -NR ¹⁰ R ¹¹ , -OR ¹² ,

R ¹⁰ and R ¹¹ are each independently selected from hydrogen, R ¹² , —C (O) R ¹² , —S (O) _n R ¹² , or in any case of —NR ¹⁰ R ¹¹ in combination (CH ₂ ) _p J (CH ₂ ) _q , where J is O, S, NH, NR ¹² or a bond,

Or R ¹² is selected from unsubstituted straight-chain, branched or cyclic C ₁ -C ₆ alkyl group, is selected from a straight, branched or cyclic C ₁ -C ₆ alkyl group substituted by no more than 5 halogen atoms,

Ar ² is selected from an unsubstituted 5- or 6-membered aromatic or heteroaromatic ring containing 0-2 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, or 0-3 nitrogen Selected from 8-membered, 9-membered or 10-membered fused aromatic or heteroaromatic ring systems containing atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, or 0-2 nitrogen atoms, 0-1 Or a 5- or 6-membered aromatic or heteroaromatic ring containing 2 oxygen atoms and 0-1 sulfur atoms, or 0-3 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms It is selected from containing 8-membered, 9-membered or 10-membered fused aromatic or heteroaromatic ring system, wherein each said Ar ² moiety is R ³ , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl , Halogen, -CN, -NO ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , May have 1 to 3 substituents selected from -OR ⁸ ,

In each case n is 0, 1 or 2,

In each case p is 2, 3 or 4,

In each case q is 0, 1 or 2.

The invention also finds use of the stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically acceptable salts of the formula (I), pharmaceutical compositions and formulations containing them, alone or in combination with other therapeutically-active compounds or substances. And methods of treating diseases and conditions, methods and intermediates used to prepare them, their use as drugs, their use in the manufacture of drugs, and their use for diagnostic and analytical purposes.

The compounds of the present invention are ligands for the nicotinic acetylcholine receptor (nAChRs) according to formula (I) and their stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically acceptable salts.

<Formula I>

Wherein Q is a residue of formula (II)

<Formula II>

-A- is selected from -O-, -S- or -NR ¹ -or is a bond directly connecting Ar ¹ and Ar ² ,

Ar ^l is selected from Formula III or Formula IV,

<Formula III>

<Formula IV>

B is O, S or NR ¹ ,

R ¹ in each occurrence is independently selected from hydrogen or R ³ ,

D is each independently selected from N or CR ² , provided that D is N in two cases or less,

R ² independently in each occurrence is hydrogen, -R ³ , -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, halogen, -CN, -NO ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , -OR ⁸ , Q or a bond, provided that R ² is in one case Q, and in one case is a bond connecting Ar ^l to A or -A- In the case of a bond, it is a bond to Ar ² ,

R ³ is selected from an unsubstituted straight, branched or cyclic C ₁ -C ₆ alkyl group, or up to 5 halogen atoms, and C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -CN, From straight, branched or cyclic C ₁ -C ₆ alkyl groups substituted with up to 2 substituents selected from -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ or -OR ⁸ Selected,

R ⁴ in each occurrence is independently selected from hydrogen, R ⁹ , —NR ¹⁰ R ¹¹ or —OR ⁸ ,

R ⁵ in each occurrence is independently selected from hydrogen, R ⁹ or —NR ¹⁰ R ¹¹ ,

R ⁶ and R ⁷ are each independently selected from hydrogen, R ⁹ , —C (O) R ⁴ or —S (O) _n R ⁵ , or in combination in any one case of —NR ⁶ R ⁷ (CH ₂ ) _p G (CH ₂ ) _q , where G is O, S, NR ⁸ or a bond,

R ⁸ is selected from hydrogen or R ⁹ ,

R ⁹ is selected from an unsubstituted straight, branched or cyclic C ₁ -C ₆ alkyl group, or up to 5 halogen atoms, and C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -CN, -NR ¹⁰ R ¹¹ , -OR ^{12 It} is selected from a straight, branched or cyclic C ₁ -C ₆ alkyl group substituted with one or more substituents,

R ¹⁰ and R ¹¹ are each independently selected from hydrogen, R ¹² , —C (O) R ¹² , —S (O) _n R ¹² , or in any case of —NR ¹⁰ R ¹¹ in combination (CH ₂ ) _p J (CH ₂ ) _q , where J is O, S, NH, NR ¹² or a bond,

Or R ¹² is selected from unsubstituted straight-chain, branched or cyclic C ₁ -C ₆ alkyl group, is selected from a straight, branched or cyclic C ₁ -C ₆ alkyl group substituted by no more than 5 halogen atoms,

Ar ² is selected from an unsubstituted 5- or 6-membered aromatic or heteroaromatic ring containing 0-2 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, or 0-3 nitrogen Selected from 8-membered, 9-membered or 10-membered fused aromatic or heteroaromatic ring systems containing atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, or 0-2 nitrogen atoms, 0-1 Or a 5- or 6-membered aromatic or heteroaromatic ring containing 2 oxygen atoms and 0-1 sulfur atoms, or 0-3 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms It is selected from containing 8-membered, 9-membered or 10-membered fused aromatic or heteroaromatic ring system, wherein each said Ar ² moiety is R ³ , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl , Halogen, -CN, -NO ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , May have 1 to 3 substituents selected from -OR ⁸ ,

In each case n is 0, 1 or 2,

In each case p is 2, 3 or 4,

In each case q is 0, 1 or 2.

Certain compounds of the present invention,

Ar ¹ is selected from Formula III or IV,

<Formula III>

<Formula IV>

B is O, S or NR ¹ ,

R ¹ in each occurrence is independently selected from hydrogen or R ³ ,

D is each independently selected from N or CR ² , provided that D is N in two cases or less,

R ² is independently at each occurrence hydrogen, -R ³ , halogen, -CN, -NO ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , -OR ⁸ , Q Or a bond, provided that R ² is Q in one case, and in one case is a bond connecting Ar ^l to A, or -A- is a bond to Ar ² ,

R ³ is an unsubstituted straight, branched or cyclic C ₁ -C ₆ alkyl group or up to 5 halogen atoms, and —CN, —C (O) R ⁴ , —S (O) _n R ⁵ , — A linear, branched or cyclic C ₁ -C ₆ alkyl group substituted with up to 2 substituents selected from NR ⁶ R ⁷ or -OR ⁸ ,

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from hydrogen or R ⁹ ,

R ⁹ is selected from unsubstituted straight chain, branched or cyclic C ₁ -C ₆ alkyl group, or up to 5 halogen atoms, and up to 1 substituent selected from -CN, -NR ¹⁰ R ¹¹ , -OR ¹² Selected from substituted straight chain, branched or cyclic C ₁ -C ₆ alkyl groups,

R ¹⁰ and R ¹¹ in each case are hydrogen,

Or R ¹² is selected from unsubstituted straight-chain, branched or cyclic C ₁ -C ₆ alkyl group, is selected from a straight, branched or cyclic C ₁ -C ₆ alkyl group substituted by no more than 5 halogen atoms,

-A- is selected from -O-, -S- or -NR ¹ -or is a bond directly connecting Ar ¹ and Ar ² ,

Ar ² is unsubstituted phenyl; 2-pyridyl, 3-pyridyl or 4-pyridyl; 2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl; 2-pyrazinyl or 3-pyrazinyl; 2-furyl or 3-furyl; 2-thiophenyl or 3-thiophenyl; 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl; 2-quinazolyl, 4-quinazolyl or 5-quinazolyl; 2-oxazolyl, 4-oxazolyl or 5-oxazolyl; 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; 1-naphthyl or 2-naphthyl; 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl; 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl or 8-isoquinolyl; 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl or 7-benzofuranyl; 2-benzo [b] thiophenyl, 3-benzo [b] thiophenyl, 4-benzo [b] thiophenyl, 5-benzo [b] thiophenyl, 6-benzo [b] thiophenyl or 7-benzo [b ] Thiophenyl; 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl; 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl or 7-benzoxazolyl; 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl or 7-benzthiazolyl, or R ³ , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkoxy Any of the above substituted with one to three substituents selected from nil, halogen, -CN, -N0 ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , -OR ⁸ Selected from an Ar ² residue,

In each case n is those according to formula (I) which are 0, 1 or 2.

Another specific compound of the invention is R ² in one case is Q, in one case a bond connecting Ar ¹ to A, and in other cases hydrogen.

Other specific compounds of the present invention are those in which Q and -A-Ar ² are in a 1,3 relationship to each other at Ar ¹ .

Another specific compound of the present invention is -A- is a bond which directly connects Ar ¹ and Ar ² .

Another compound of the present invention is that Ar ¹ is a residue of formula III.

Another compound of the invention is that Ar ¹ is a furan ring.

Another compound of the invention is that Ar ¹ is a thiophene ring.

Another compound of the invention is Ar ¹ is a residue of formula III and B is O.

Another compound of the invention is Ar ¹ is a residue of formula III and B is S.

In addition, another compound of the present invention is Ar ¹ is a residue of formula III, D is CR ² , where R ² is Q in one case, and in one case is a bond connecting Ar ¹ to A, in other cases hydrogen It is

Another compound of the present invention,

R ³ is methyl, ethyl,

Linear, cyclic or branched propyl, butyl, pentyl or hexyl,

Ethenyl, 1-propenyl, 2-propenyl or 3-propenyl,

Linear, branched or cyclic butenyl, pentenyl or hexenyl,

Ethynyl or propynyl,

Chloro, bromo, fluoro, iodo, -CN, -N0 ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ or -OR ⁸ ,

R ⁴ is independently at each occurrence hydrogen, R ⁹ , —NR ¹⁰ R ¹¹ , —OR ⁸ , trifluoromethyl, trifluoroethyl, methoxymethyl, trifluoromethoxymethyl, methoxyethyl or trifluoromethoxy Selected from ethyl,

R ⁵ in each occurrence is independently selected from hydrogen, R ⁹ or —NR ¹⁰ R ¹¹ ,

R ⁶ and R ⁷ are each independently selected from hydrogen, R ⁹ , —C (O) R ⁴ or —S (O) _n R ⁵ , or in combination in any one case of —NR ⁶ R ⁷ (CH ₂ ) _p G (CH ₂ ) _q , where G is O, S, NR ⁸ or a bond,

R ⁸ is selected from hydrogen or R ⁹ ,

R ⁹ is methyl, ethyl,

Linear, cyclic or branched propyl, butyl, pentyl or hexyl,

Ethenyl, 1-propenyl, 2-propenyl or 3-propenyl,

Linear, branched or cyclic butenyl, pentenyl or hexenyl,

Selected from ethynyl or propynyl, wherein any of the R ⁹ residues is chloro, bromo, fluoro, up to 5 iodo atoms, and one substituent selected from -CN, -NR ¹⁰ R ¹¹ , -OR ¹² May contain

R ¹⁰ and R ^ll are each independently selected from hydrogen, R ¹² , —C (O) R ¹² , —S (O) _n R ¹² , or in combination in any one case of —NR ⁶ R ⁷ (CH ₂ ) _p J (CH ₂ ) _q , where J is O, S, NR ¹² or a bond,

R ¹² is methyl, ethyl,

Linear, cyclic or branched propyl, butyl, pentyl or hexyl,

Ethenyl, 1-propenyl, 2-propenyl or 3-propenyl,

Linear, branched or cyclic butenyl, pentenyl or hexenyl,

Selected from ethynyl or propynyl, wherein any of the R ¹² residues may contain up to 5 chloro, bromo, fluoro, iodo atoms,

Ar ² is unsubstituted phenyl; 2-pyridyl, 3-pyridyl or 4-pyridyl; 2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl; 2-pyrazinyl or 3-pyrazinyl; 2-furyl or 3-furyl; 2-thiophenyl or 3-thiophenyl; 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl; 2-quinazolyl, 4-quinazolyl or 5-quinazolyl; 2-oxazolyl, 4-oxazolyl or 5-oxazolyl; 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; 1-naphthyl or 2-naphthyl; 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl; 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl or 8-isoquinolyl; 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl or 7-benzofuranyl; 2-benzo [b] thiophenyl, 3-benzo [b] thiophenyl, 4-benzo [b] thiophenyl, 5-benzo [b] thiophenyl, 6-benzo [b] thiophenyl or 7-benzo [b ] Thiophenyl; 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl; 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl or 7-benzoxazolyl; 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl or 7-benzthiazolyl; Or any of the above Ar ² residues substituted with 1, 2 or 3 R ³ substituents.

Certain compounds of the present invention

(R) -3 '-(5-phenylthiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (4-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (3-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one , And

(R) -3 '-[5- (2-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one This includes.

In another aspect, the invention relates to compounds according to formula (I) and their use in therapy and compositions containing them.

In a further aspect, the invention relates to compounds according to formula (I), wherein at least one element is labeled with a radioisotope of the same element. In certain forms of this aspect of the invention, the compound of formula (I) is labeled with tritium.

Compounds of the invention labeled with tritium are useful for the discovery of novel pharmaceutical compounds that bind to the α7 nicotinic acetylcholine receptor and modulate their activity by their agonist action, partial agonist action or antagonism. Such tritium-labeled compounds can be used in assays to determine the substitution of such compounds to analyze the binding of ligands that bind to the α7 nicotinic acetylcholine receptor.

In certain aspects, the present invention relates to the use of a compound according to formula (I) for the treatment of diseases mediated through the action of nicotinic acetylcholine receptors. In a more particular aspect, the present invention relates to the use of a compound of formula (I) for the treatment of a disease mediated through the action of an a7 nicotinic acetylcholine receptor.

In another aspect, the present invention relates to a method of treating or preventing a disease or condition in humans in which activation of the a7 nicotinic receptor is advantageous, comprising administering a therapeutically effective amount of a compound of the present invention.

In another aspect, the present invention relates to a method of treating or preventing a nervous system disorder, a psychotic disorder or an intellectual impairment disorder comprising administering a therapeutically effective amount of a compound of the present invention.

In another aspect, the present invention relates to a method of treating or preventing Alzheimer's disease, learning deficiency, cognitive deficit, attention deficit, memory loss or attention deficit hyperactivity disorder.

In another aspect, the present invention relates to a method of treating or preventing neurodegenerative disorders with Parkinson's disease, Huntington's disease, Tourette's syndrome or cholinergic synapse loss.

 In another aspect, the present invention relates to a method of treating or preventing anxiety, schizophrenia or manic depression.

In another aspect, the present invention relates to a method for the treatment or prevention of jet lag, smoking cessation, nicotine intoxication, craving, pain and ulcerative colitis, comprising administering a therapeutically effective amount of a compound of the invention.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.

In a further aspect, the present invention provides a therapeutically or prophylactically effective amount for a disorder or condition referred to herein for the treatment or prevention of a condition or disorder referred to herein arising from a dysfunction of nicotinic acetylcholine receptor neurotransmission in a mammal, preferably a human. A pharmaceutical composition comprising a compound of formula (I), an enantiomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention relates to the use of a pharmaceutical composition of the invention for the treatment or prevention of a disease or condition in humans in which the activation of the a7 nicotinic receptor is advantageous.

In another aspect, the invention relates to the use of a pharmaceutical composition of the invention for the treatment or prevention of a neurological disorder, a psychotic disorder or an intellectual impairment disorder.

In another aspect, the invention provides Alzheimer's disease, learning deficiency, cognitive deficit, attention deficit, memory loss, attention deficit hyperactivity disorder, anxiety, schizophrenia, manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome, loss of cholinergic synapse The present invention relates to the use of the pharmaceutical composition of the present invention for the treatment and prevention of nicotine poisoning, craving, pain and ulcerative colitis, including neurodegenerative disorders, jet lag, smoking cessation, exposure to products containing nicotine. .

A further aspect of the present invention is the use of the compounds of the present invention, their enantiomers or their pharmaceutically acceptable salts in the manufacture of a medicament for the treatment or prevention of the above mentioned diseases or conditions.

In another aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease or condition in humans in which activation of the a7 nicotinic receptor is advantageous.

In another aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a neurological disorder, a psychotic disorder or an intellectual impairment disorder.

In another aspect, the present invention relates to the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of Alzheimer's disease, learning deficiency, cognitive deficit, attention deficit, memory loss or attention deficit hyperactivity disorder.

In another aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of anxiety, schizophrenia or mood swings.

In another aspect, the present invention relates to the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of Parkinson's disease, Huntington's disease, Tourette's syndrome or neurodegenerative disorders with loss of cholinergic synapses.

In another aspect, the present invention relates to the use of a compound described above in the manufacture of a drug for the treatment or prevention of jet lag, pain or ulcerative colitis.

In another aspect, the present invention relates to the use of a compound of the present invention in the manufacture of a medicament for the treatment of nicotine poisoning or craving, including facilitating quitting smoking or due to exposure to a product containing nicotine.

For the uses, methods and compositions referred to herein, the dose administered will of course vary depending on the compound used, the mode of administration and the desired treatment. However, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of about 0.1 mg to about 20 mg per kg body weight of the animal. Such dosages may be administered in 1 to 4 divided doses per day or sustained release. For men, the total daily dose is in the range of 5 mg to 1,400 mg, more preferably 10 mg to 100 mg, and a suitable unit dose for oral administration is 2 mg of a compound mixed with a solid or liquid pharmaceutical carrier or diluent To 1,400 mg.

The compounds of formula (I), their enantiomers and their pharmaceutically acceptable salts can be used alone or in the form of suitable pharmaceutical formulations for oral or parenteral administration. According to a further aspect of the present invention there is provided a pharmaceutical composition comprising preferably less than 80%, more preferably less than 50% by weight of a compound of the present invention in a mixture with a pharmaceutically acceptable inert diluent or carrier. Examples of diluents and carriers are as follows.

-Tablets and dragees: lactose, starch, talc, stearic acid

-For capsule: tartaric acid or lactose

-For injection: water, alcohol, glycerin, vegetable oil

-Suppository: natural oil, hardened oil or wax

Also provided is a method of making such a pharmaceutical composition comprising a mixture of components.

The compounds according to the invention are agonists of nicotinic acetylcholine receptors. Without being limited by theory, compounds and / or their agonists of the α7 nAChR (nicotinic acetylcholine receptor) subtype are useful for the treatment or prevention of neurological, psychotic and intellectual impairment disorders, and are the α4 nAChR subtype. It is thought to have an advantage over agonists. Thus, compounds that are selective for the α7 nAChR subtype are preferred. The compounds of the present invention are particularly shown as pharmaceuticals in the treatment or prevention of neurological disorders, psychotic disorders and intellectual impairment disorders. Examples of psychotic disorders include schizophrenia, mood swings, and anxiety. Impairment of intelligence includes Alzheimer's disease, learning deficiency, cognitive deficit, attention deficit, memory loss and attention deficit hyperactivity disorder. The compounds of the present invention may also be useful as analgesics in the treatment of pain (including chronic pain) and in the treatment or prevention of neurodegenerative disorders with Parkinson's disease, Huntington's disease, Tourette's syndrome and cholinergic synapses. The compounds may additionally be presented for the treatment or prevention of jet lag, induction of smoking cessation, use in craving, and the treatment or prevention of nicotine addiction (including due to exposure to nicotine containing products).

It is also contemplated that the compounds according to the invention will be useful for the treatment and prevention of ulcerative colitis.

As used herein, "C _{1 -6} alkyl" term represents a straight-chain, branched or cyclic C _{1 -6} alkyl group;

As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

Manufacturing method

Methods that can be used for the synthesis of the compounds of formula (I) include the methods A, B, C and D described below. In this method, unless otherwise specified, Ar ¹ , Ar ² and A are the same as defined in formula (I) above.

Method A

In formula (VI) of Scheme 1, E represents an R ² residue at Ar ¹ which becomes R ² represented by Q in formula (I). In formula (VI), E is a halogen or OSO ₂ CF ₃ group.

Compounds of formula I can be prepared by treating compounds of formula V with compounds of formula VI in the presence of a base. In order to carry out this reaction, the presence of a catalyst such as an organometallic catalyst may facilitate the reaction or may be necessary to induce the reaction. Suitable organic bases include lithium, sodium or potassium bases including hydrides, alkoxides, hydroxides, carbonates, amides, alkylamides or alkyls. Suitable catalysts include copper, palladium or nickel compounds. The catalyst may be an organometallic complex that is preformed with a metal, salt, or organometallic compound or formed in situ by addition of a ligand. Suitable ligands include diamine ligands (such as 1,2-diaminoethane or 1,2-diaminocyclohexane) or phosphine ligands (such as triphenylphosphine). Preferred base is potassium carbonate. Preferred catalysts are copper (I) iodide. The reaction is preferably carried out in the presence of ethylenediamine as ligand. The reaction is carried out in an inert solvent. Preferred inert solvents are 1,4-dioxane. The reaction is carried out at about 100 ° C.

Method B

In the formula (VII) of Scheme 2, H ₂ N-Ar ¹ represents the R ² residue at Ar ¹ to be R ² represented by Q of formula (I). Likewise, in Formula (V), Ar ¹ is linked to the nitrogen of aminoalcohol at the position of Ar ¹ which is Q in the compound of Formula (I).

Method B can be carried out in two steps: ring opening the epoxide VII to compound VII, followed by carbonylating the resulting intermediate VII to form an oxazolidinone ring of the compound of formula (I).

Formula (VIII) compounds can be prepared by treating compounds of Formula (V) with compounds of Formula (VIII). In order to carry out the reaction, the presence of a base may facilitate the reaction and is necessary to carry out the reaction, and may be desirable or necessary to form the amide anion of compound (VII). Suitable organic bases include alkali metal bases including hydrides, alkoxides, alkylamides or alkyls. Preferred bases are strong bases such as alkyllithium bases, or lithium dialkylamides, or sodium hydrides or potassium hydrides. The reaction is carried out in an inert solvent. Preferred inert solvents are tetrahydrofuran.

Compounds of formula (I) may be prepared by treating compounds of formula (VII) with carbonyl donor compounds. Examples of carbonyl donor compounds include carbonyldiimidazole, carbonyldichloride (phosgene) and triphosgene. The reaction is carried out in an inert solvent such as tetrahydrofuran or toluene. The reaction is carried out at elevated temperature, for example by refluxing tetrahydrofuran or toluene.

Method C

Method C can be carried out in three steps: forming an amide bond between the carboxylic acid derivative of formula (VII) and the compound of formula (VII), reducing the carbonyl group of the resulting amide of formula (XI), wherein G is a leaving group Carbonylating the resulting aminoalcohol of formula (VII) to form an oxazolidinone ring of formula (I).

In formula (VIII), Ar ¹ is linked with an amide nitrogen at the position of Ar ¹ to be Q in the compound of formula (I). That is, in formula (V), R ² is a bond connecting Ar ¹ and amide nitrogen.

In the compounds of formula (VII), suitable leaving groups G for the preparation of the amides of formula (XI) from the compounds of formula (X) and the carboxylic acid derivatives of formula (X) include OH, halogen, Oalkyl, Oaryl, OCOalkyl, OCOaryl . The reaction is carried out by mixing the compounds of formulas (VII) and (VII) in a suitable solvent and maintaining the mixture at 0 to 100 ° C. The presence of a coupling agent when the base or G is OH may be necessary to cause the reaction. Suitable bases for the reaction include 4- (N, N-dimethylamino) pyridine, pyridine, triethylamine, N, N-diisopropylethylamine. Preferred base is N, N-diisopropylethylamine. Suitable coupling agents when G is OH include carbodiimide (eg 1,3-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride), phosphonium reagents ( For example benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) and uronium reagents (e.g. O -Benzo-triazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate) Preferred coupling agents are O-benzotriazol-1-yl-N, N , N ', N'-tetramethyluronium tetrafluoroborate Suitable solvents for the reaction include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or chloroform Preferred solvents are N, N- Dimethylformamide The reaction is preferably within zero. To 50 ° C., and most preferably at a temperature of 20 to 30 ° C.

The conversion of the amide of formula (XI) to the amino alcohol of formula (VII) by reduction of the carbonyl group can be carried out by treating the amide with a suitable reducing agent in a suitable solvent. Suitable reducing agents include aluminum hydride and lithium aluminum hydride. Suitable solvents include ether solvents such as tetrahydrofuran.

Compounds of formula (VII) may be treated with the carbonyl donor compounds described in Method B above to produce compounds of formula (I).

Method D

In Formula XII of Scheme 4, Ar ¹ -X represents an OR ² residue in Ar ¹ , where R ² is a bond that is linked to the A residue of the compound of Formula I. That is, Ar ¹ in Formula XII is connected to X at the position of Ar ¹ connected to A in the compound of Formula I.

(i) A is bonded

Compounds of formula (I) wherein A is a bond may be prepared by cross-coupling reactions of compounds of formulas (XII) and (XIII), wherein one of X or Y is halogen or OSO ₂ CF ₃ , where Y or X are each an organometallic group to be. Suitable organometallic groups include boronic acid or boronic ester groups, B (OH) ₂ , B (OR) ₂ or trialkylstannyl groups SnR ₃ , where R is an alkyl group. The reaction is carried out in the presence of a suitable organometallic catalyst and a solvent. Suitable organometallic catalysts include palladium (0) complexes (e.g. tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0)) and suitable triarylphosphines or triaryl ars. Combinations of renal ligands (eg triphenylphosphine, tri (o-tolyl) phosphine or triphenylarcin). Suitable solvents include inert ether solvents (eg 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane) or alcohols (such as ethanol) or mixtures thereof. If the compound of formula (XI) or (XII) is boronic acid, the presence of a suitable base in addition to other reagents is preferred. Suitable bases include sodium carbonate, cesium carbonate and barium hydroxide. The reaction is carried out at a temperature of 0 to 120 ° C, preferably 60 to 120 ° C.

Compounds of formula (XII) wherein X is an organometallic group or compounds of formula (XIII) wherein Y is an organometallic group may be prepared by suitable metallization or exchange procedures from compounds of the corresponding formula wherein X or Y is hydrogen, halogen or OSO ₂ CF ₃ Can be. Compounds having an organometallic group B (OH) ₂ are prepared by converting the corresponding aryllithium or arylmagnesium from a suitable aromatic compound having a hydrogen or halogen group, followed by reaction with trialkylborate and subsequent hydrolysis of the resulting borate ester. Can be. Similarly, compounds in which the organometallic group is a trialkylstannyl group can be prepared by converting from a suitable aromatic compound having a hydrogen or halogen group to the corresponding aryllithium or arylmagnesium compound and then reacting with a suitable trialkylstannyl halide. The formation of aryllithium or arylmagnesium compounds is carried out in a suitable inert solvent such as tetrahydrofuran. Alternatively, compounds having an organometallic group B (OH) ₂ are prepared by reaction with bis (pinacolato) diborone and organometallic catalysts from a suitable aromatic compound having a halogen or OS0 ₂ CF ₃ group, followed by hydrolysis of the resulting borate ester. The compound wherein the organometallic short term is a trialkylstannyl group may be prepared by reaction with a suitable bis (trialkyltin) in the presence of a suitable organometallic catalyst from a suitable aromatic compound having a halogen or OSO ₂ CF ₃ group have. The reaction is carried out in a suitable inert solvent such as tetrahydrofuran, and suitable organometallic catalysts include, for example, tetrakis (tripetylphosphine). The reaction is carried out at a temperature of about 0 to about 150 ° C, preferably about 20 to about 100 ° C. Typical procedures for performing such transformations will be known to those skilled in the art.

(Ii) A NR ^One

Compounds of formula I wherein A is NR ¹ may be prepared by cross coupling reactions of compounds of formulas XII and XIII, wherein either X or Y is halogen or OSO ₂ CF ₃ , where Y or X are each NHR ¹ The reaction can be carried out by heating in an inert solvent in the presence of a strong base. Suitable inert solvents include ether solvents (eg tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or di (2-methoxyethyl) ether), hydrocarbon solvents (eg benzene or toluene) Or amide solvents (eg dimethylformamide or N-methyl-2-pyrrolidinone). Preferred solvent is tetrahydrofuran. Suitable strong bases include alkali metal alkoxides or amide bases (eg sodium t-butoxide or potassium t-butoxide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide). Preferred strong bases are sodium t-butoxide. The reaction may require the presence of an organometallic catalyst, and may preferably be carried out in the presence of an organometallic catalyst. Suitable organometallic catalysts include complexes of palladium (0) with suitable phosphine ligands, preferably triarylphosphine ligands, most preferably triarylphosphine bidentate ligands. Preferred ligands include 2,2'-bis (diphenylphosphino) -1,1'-binafyl or 1,1'-bis (diphenylphosphino) ferrocene. The catalyst may be synthesized by a combination of a suitable source of palladium (0) (eg tris (dibenzylideneacetone) dipalladium (0)) with a phosphine ligand, pre-formed or added to the reaction mixture and a palladium source and It can be formed in situ by including a phosphine ligand. The reaction is carried out at a temperature of about 0 to 150 ° C and preferably about 60 to 120 ° C.

(Iii) A is O or S

Compounds of formula I, wherein A is O or S, can be prepared by cross-coupling reactions of compounds of formulas XII and XIII, wherein either X or Y is halogen or OS0 ₂ CF ₃ , where Y or X are each OH or SH. The reaction can be carried out by heating in an inert solvent in the presence of a base. The reaction may require the presence of a catalyst and when A is O, the reaction is preferably carried out in the presence of a catalyst. Suitable inert solvents include ether solvents (eg tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or di (2-methoxyethyl) ether), amide solvents (eg dimethylformamide or N-methyl-2-pyrrolidinone) or basic heterocyclic aromatic solvent (eg pyridine). Preferred solvent is pyridine. Suitable bases include alkali metal alkoxides or alkali metal carbonates (eg potassium carbonate). Suitable organometallic catalysts include copper or salts thereof, preferably copper (I) salts, and most preferably copper (I) iodide. The reaction is carried out at a temperature of about 0 to 150 ° C, and preferably about 100 to 150 ° C.

Certain compounds of formula (XII), wherein X is halogen, can be prepared from the compounds of formula (XII), wherein X is hydrogen, by reaction with a suitable halogenating agent in a suitable solvent. Suitable halogenating agents include bromine or other halogen elements. Suitable solvents include acetic acid. The reaction is preferably carried out at temperatures from 0 to 50 ° C. and most preferably from 0 to 25 ° C.

Compounds of formula (XII), wherein X is OS0 ₂ CF ₃ , may be prepared from compounds of formula (XII), wherein X is OH, by reaction with trifluoromethanesulfonic anhydride or other trifluoromethanesulfonating agents in the presence of a base and a solvent. . Suitable bases include pyridine and 2,6-di-t-butylpyridine. The reaction is preferably carried out at a temperature of -78 to 120 ° C and most preferably at -78 to 0 ° C.

Certain compounds of formula (XII), wherein X is hydrogen, halogen, OSO ₂ CF ₃ , NHR ¹ , OH or a suitable organometallic group, are described under methods A-C above, wherein X is substituted with A-Ar ² in the formulas shown in Schemes 1-3. It can be prepared by a similar method.

Compounds of formula (XIII) wherein Y is hydrogen, halogen, OSO ₂ CF ₃ , NHR ¹ , OH or a suitable organometallic group are commercially available, described in synthetic organic chemistry literature, or known to those skilled in the methods or synthetic organic chemistry described herein. It can be produced by the method.

Method E

In formula (XIV) in Scheme 5, RO ₂ CNH-Ar ¹ represents the residue R ² at Ar ¹ to be R ² represented by Q of formula (I). R represents an aliphatic or aromatic group, and the residue RO ₂ C can thus act as an intramolecular carbonylating agent with OR removed as a leaving group. Suitable R groups include simple alkyl and aryl groups such as methyl, ethyl or phenyl. Preferred R groups are methyl.

Method E involves a chemical modification consisting of two reactions: ring opening epoxide VII to compound XIV, followed by cyclization to form an oxazolidinone ring of the compound of formula (I). Method E is similar to method B, except that the RO ₂ C group in compound XIV provides a carbonyl group rather than a subsequent carbonylation step. The two reactions can be carried out in a single step combining VII and XIV in the presence of a catalyst, preferably in a single step. Suitable catalysts include basic catalysts or phase transfer catalysts. The reaction is carried out in an inert solvent. The reaction is preferably carried out using a phase transfer catalyst such as tetra-n-butylammonium chloride with water as solvent. The reaction is preferably carried out at elevated temperature. For example, when the reaction is carried out in water, the reaction is preferably carried out at 100 ° C.

Compounds of formula (VI), (VIII) and (XIV) are commercially available, described in synthetic organic chemistry literature, or prepared by methods known to those skilled in the synthetic organic chemistry art. The compounds may also be prepared from simple precursors in which the linkage of Ar ¹ and Ar ² by linking group A is formed by cross-coupling by a method similar to that described in Method D herein, wherein the precursor is commercially available, It is prepared by methods described in the synthetic organic chemistry literature or known to those skilled in the synthetic organic chemistry art.

Those skilled in the art will appreciate that aromatic substituents in the compounds of the present invention or intermediates used in the synthesis of the compounds of the present invention may be introduced using aromatic substitution reactions, functional group modifications for altering existing substituents, or combinations thereof. This reaction can be achieved before or immediately after the abovementioned method. Reagents and reaction conditions for this procedure are known in the art. Specific examples of procedures that can be used include, for example, electrophilic functionalization of aromatic rings by nitration, halogenation or acylation; Modification of the nitro group to an amino group, for example by reduction (such as catalytic hydrogenation); Acylation, alkylation, sulfonylation of amino or hydroxy groups; Substitution of the amino group with another functional group by nucleophilic or free radical substitution of the diazonium salt after conversion to the intermediate diazonium salt; Or substitution of halogen with other functional groups, for example by substitution reactions catalyzed by nucleophilic or organometallics.

If desired, hydroxy, amino or other reactive groups can be protected using protecting groups by standard techniques. Unless stated otherwise, the reactions described above are usually carried out at about 1 to 3 atmospheres, preferably at atmospheric pressure (about 1 atmosphere).

If not mentioned otherwise, the reaction described above is carried out in an inert atmosphere, preferably in a nitrogen atmosphere.

Compounds and intermediates of the invention can be isolated from the reaction mixture by standard techniques.

Acid addition salts of compounds of formula I which may be mentioned include salts of inorganic acids (eg hydrochloride and hydrobromide salts) and salts formed with organic acids (eg formate, acetate, maleate, benzoate, tartrate and fumarate). Salts).

Acid addition salts of compounds of formula I can be formed by reacting the free base, or salts, enantiomers or protected derivatives thereof, with at least one equivalent of acid. The reaction can be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble (eg water, dioxane, ethanol, tetrahydrofuran or diethyl ether or a mixture of solvents), in vacuo or Can be removed by freeze drying. The reaction may be a metathesis method or may be carried out in an ion exchange resin.

Compounds of formula I exist in tautomeric or enantiomeric forms, all of which are included within the scope of the invention. Various optical isomers can be isolated by decomposing the racemic mixture of the compounds using conventional techniques such as fractional crystallization or chiral HPLC. Alternatively, each enantiomer can be prepared by reaction of a suitable optically active starting material under reaction conditions that will not cause racemization.

Commercial reagents were used without further purification. Mass spectra were recorded using an HP-1100 HPLC and an HPLC-MS system using a Micromass LCZ mass spectrometer using APCI as the ionization technique, and recorded in m / z for parent molecular ions. Room temperature represents 20-25 degreeC. (S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and other precursors are described in Mullen et al. (2000) J. Med. Chem. 43, 4045-4050. The radiolabelled forms of the example compounds are useful for the search for new drug compounds that bind to the α7 nicotinic acetylcholine receptor and modulate its activity by agonist action, partial agonist action, or antagonism. Such radiolabeled compounds are synthesized by either the incorporation of radiolabeled starting materials or the exchange of hydrogen to tritium by known methods in the case of tritium. Known processes include (1) electrophilic halogenation followed by reduction of halogen in the presence of a tritium source, for example hydrogenation with tritium gas in the presence of a palladium catalyst, or (2) tritium gas and a suitable organic metal. Exchange of hydrogen for tritium carried out in the presence of a (eg palladium) catalyst.

Manufacture 1

(R) -3 '-(thiophen-2-yl) Spiro [l- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one (505 mg, 3. 58 mmol), 5-bromothiophene (1.75 g, 10.74 mmol), copper (I) iodide (69 mg, 0.36 mmol) and potassium carbonate (495 mg, 3.58 mmol) were stirred at 120 ° C. overnight. After cooling to rt, the mixture was purified by flash chromatography using a gradient of concentration of ammonia methanol in chloroform to give the title compound (450 mg) as m / z 265 (MH ⁺ ) as a yellow solid.

Manufacture 2

(R) -3 '-(5- Bromothiophene -2 days) Spiro [l- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(thiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one (425 mg, 1.61 mmol) and N-bromosuccinimide (287 mg, 1.61 mmol) was stirred for 3 h at 80 ° C. in DMF (7 mL). The mixture was allowed to cool to rt, then diluted with chloroform, washed with aqueous potassium carbonate, then brine, then dried (magnesium sulphate), filtered and evaporated. The residue was purified by flash chromatography using a gradient of ammonia methanol in chloroform to give the title compound (415 mg) as m / z 343,345 (MH ⁺ ) as a yellow solid.

Manufacture 3

(R) -3 '-(4- Bromothiophene -2-yl) spiro [l- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(S) -spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one (471 mg, 2.58 mmol), 2,4-dibromothiophene (1.875 g , 7.75 mmol), copper (I) iodide (492 mg, 2.58 mmol), potassium carbonate (715 mg, 5.17 mmol) and ethylenediamine (170 μL, 2.58 mmol) were prepared in 1,4-dioxane (5 mL) at 110 ° C. overnight. The solution was allowed to cool, then filtered, washed with aqueous ammonium hydroxide and evaporated. The residue was purified by flash chromatography using a gradient of concentration of ammonia methanol in chloroform to give the title compound (560 mg) as m / z 343,345 (MH ⁺ ) as a yellow solid.

Manufacture 4

(R) -3 '-(furan-2-yl) Spiro [l- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

The title compound was prepared by a method analogous to that described in Preparation 3 from (S) -spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 2-bromofuran. Prepared. The title compound (1.49 g) was obtained as light yellow solid, m / z 249 (MH ⁺ ).

Manufacture 5

(R) -3 '-(5- Bromofuran -2 days) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazole Lidine ] -2'-on

From (R) -3 '-(furan-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one in a method analogous to that described in Preparation 2 To give the title compound. The title compound (1.70 g) was obtained as pale yellow solid, m / z 327,329 (MH ⁺ ).

Manufacture 6

(R) -3 '-[4- Bromo -5- ( Trimethylsilyl ) Furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 2,4- Dibromo -5- ( Trimethylsilyl Furan

To a solution of 2,3-dibromofuran (5.0 g, 22.14 mmol) in anhydrous ether (20 mL) stirred at −78 ° C., 1.8 M, 16.0 in lithium diisopropylamide (heptane / tetrahydrofuran / ethylbenzene mL, 28.8 mmol) was added. After 10 minutes, trimethylsilyl chloride (3.65 mL, 28.8 mmol) was added at -78 ° C, then the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride and then the reaction mixture was partitioned between water and ether. The ether layer was washed with water and then dried (magnesium sulphate), filtered and the solvent was evaporated. The residue was purified by flash chromatography using hexanes to give the subtitle compound (8.50 g) as m / z 297,299,301 (MH ⁺ ) as a yellow oil. The crude product was used in the next step without further purification.

(b) (R) -3 '-[4- Bromo -5- ( Trimethylsilyl ) Furan-2-yl] Spiro [One- Azabicyclo [2. 2.2] octane -3,5'- Oxazolidine ] -2'-on

Prepared from (S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 2,4-dibromo-5- (trimethylsilyl) furan 3 The title compound was prepared by a method similar to that described in. The title compound (577 mg) was obtained as pale yellow solid, m / z 399,401 (MH ⁺ ).

Manufacture 7

(R) -3 '-(4- Bromofuran -2 days) Spiro [l- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-[4-bromo-5- (trimethylsilyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5' in tetrahydrofuran (5 mL) To a solution of -oxazolidin] -2'-one (577 mg, 1.44 mmol) was added tetra-n-butylammonium fluoride (1 M solution in tetrahydrofuran, 2.2 mL, 2.20 mmol). The solution was heated at 70 ° C. (bath temperature) for 6 hours. The reaction mixture was evaporated to dryness and the residue was subjected to flash chromatography using a gradient of ammonia methanol in chloroform as eluent to afford the title compound (387 mg) as m / z 327,329 (MH ⁺ ) as a pale brown solid. .

Manufacture 8

3 '-(thiazol-2-yl) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) methyl  N- (thiazol-2-yl) Carbamate

The catalytic amount of 2-aminothiazole (10.00 g, 99.86 mmol), triethylamine (20.2 g, 200 mmol) and 4- (N, N-dimethylamino) pyridine was added at 0 ° C. in anhydrous tetrahydrofuran (200 mL). Stirred. Methyl chloroformate (18.9 g, 200 mmol) was added slowly to the mixture at 0 ° C. The reaction mixture was then stirred for several hours at room temperature. Tetrahydrofuran was evaporated and the residue was dissolved in chloroform, the resulting solution was washed with water, dried over magnesium sulphate and filtered, then the solvent was evaporated. The residue was purified by flash chromatography using a concentration gradient of ammonia methanol in chloroform to give the subtitle compound (17.0 g) as m / z 159 (MH ⁺ ) as a pale yellow solid.

(b) 3 '-(thiazol-2-yl) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2 '-on

Spiro [1-azabicyclo [2.2.2] octane-3,2'-oxirane] -N1-trihydroborone (3.00 g, 19.6 mmol), methyl N- (thiazol-2-yl) -carbamate (3.90 g, 23.5 mmol) and tetra-n-butylammonium chloride (1.09 g, 3.92 mmol) were suspended in water (30 mL) and the reaction mixture was stirred at 80 ° C. overnight. After cooling to room temperature, the reaction mixture was filtered and the combined solids were washed with a small amount of water. The solid was then dissolved in acetone (60 mL) and 6 mL concentrated hydrochloric acid was added. The mixture was stirred at rt overnight. The solvent was evaporated from the mixture, and then the residue was partitioned between potassium carbonate and chloroform. The chloroform layer was dried over magnesium sulfate, filtered and evaporated to afford the title compound (3.30 g) as m / z 266 (MH ⁺ ) as a light solid.

Manufacture 9

3 '-(5- Bromothiazole -2 days) Spiro [l- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

Method I

3 '-(thiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one (2.80 g, 10.55 mmol) and N-bromo The solution containing succinimide (3.90 g, 21.86 mmol) was stirred overnight at RT in N, N-dimethylformamide (15 mL). The mixture was diluted with chloroform and washed with saturated aqueous potassium carbonate and then brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified by flash chromatography using a concentration gradient of ammonia methanol in chloroform to give the title compound (1.70 g) as m / z 343,345 (MH ⁺ ) as a light solid.

Method II

(a) methyl  N- (5- Bromothiazole -2 days) Carbamate

The title compound was prepared in a similar manner to that of Preparation 8 (a) from 2-amino-5-bromothiazole. The title compound (4.10 g) was obtained as a yellow solid, m / z 237,239 (MH ⁺ ).

(b) 3 '-(5- Bromothiazole -2 days) Spiro [l- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

Prepared from spiro [1-azabicyclo [2.2.2] octane-3,2'-oxirane] -N1-trihydroboron and methyl N- (5-bromothiazol-2-yl) carbamate 8 (b The title compound was prepared in a similar manner as described in The title compound (650 mg) was obtained as light solid, m / z 344,346 (MH <+>).

Example  One

(R) -3 '-(5- Phenylthiophene -2 days) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] in ethanol / 1,2-dimethoxyethane (1: 4 v / v; 2 mL) Octane-3,5'-oxazolidine] -2'-one (80 mg, 0.23 mmol), phenylboronic acid (31 mg, 0.26 mmol), potassium carbonate (105 mg, 0.76 mmol) and tetrakis ( Triphenylphosphine) palladium (0) (7 mg, 0.006 mmol) was heated at reflux for 4 hours at reflux. The solution was allowed to cool, then filtered and evaporated. Purification was carried out by flash chromatography using a concentration gradient of ammonia methanol in chloroform to give the title compound (59 mg) as m / z 341 (MH ⁺ ) as a pale yellow solid.

Example  2

(R) -3 '-[5- (4- Pyridyl ) Thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromo-thiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and pyridine- The title compound was prepared from 4-boronic acid by a method similar to that described in Example 1. The title compound (34 mg) was obtained as pale yellow solid, m / z 342 (MH ⁺ ).

Example  3

(R) -3 '-[5- (3- Pyridyl ) Thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and pyridine-3- The title compound was prepared from boronic acid by a method similar to that described in Example 1. The title compound (24 mg) was isolated as m / z 342 (MH ⁺ ) as hydrochloride salt as off-white solid.

Example  4

(R) -3 '-[5- (2- Pyridyl ) Thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa zolidin] -2'-one (108 mg, 0.31 mmol), 2-tri-n-butylstannylpyridine (218 mg, 0.50 mmol) and tetrakis (triphenylphosphine) palladium (0) (36 mg, 0.03 mmol) at 100 ° C. in toluene (3.5 mL) Heated for 5 hours. The solution was filtered and then purified by flash chromatography using a concentration gradient of ammonia methanol in chloroform to give the title compound (73 mg) as m / z 342 (MH ⁺ ) as a light solid.

Example  5

(R) -3 '-[5- (thiophen-2-yl] thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane-3, 5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri The title compound was prepared by a method analogous to that described in Example 4 from -n-butylstannyl) thiophene. The solid obtained from flash chromatography was further purified by reverse phase HPLC on a C ₁₈ column using a concentration gradient of 5 to 45% acetonitrile / water as eluent (each solvent containing 0.1% trifluoroacetic acid as buffer). I was. Product-containing fractions were evaporated. The residue was partitioned between saturated aqueous potassium carbonate and chloroform, then the chloroform layer was dried (magnesium sulphate), filtered and evaporated to give the title compound (100 mg) as m / z 347 (MH ⁺ ) as off-white solid. .

Example  6

(R) -3 '-[5- (thiophen-3-yl) thiophen-2-yl] Spiro [l- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and thiophen-3 The title compound was prepared from boronic acid by a method similar to that described in Example 2. The title compound (118 mg) was obtained as a light solid, m / z 347 (MH ⁺ ).

Example  7

(R) -3 '-[5- (furan-2-yl) thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri The title compound was prepared by a method analogous to that described in Example 5 from -n-butylstannyl) furan. The title compound (52 mg) was obtained as a light solid, m / z 347 (MH ⁺ ).

Example  8

(R) -3 '-[5- (furan-3-yl) thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and furan-3- The title compound was prepared from boronic acid by a method similar to that described in Example 2. The title compound (45 mg) was obtained as a light solid, m / z 347 (MH ⁺ ).

Example  9

(R) -3 '-[5- (thiazol-2-yl) thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri The title compound was prepared by a method analogous to that described in Example 5 from -n-butylstannyl) thiazole. The title compound (9 mg) was obtained as light solid, m / z 348 (MH ⁺ ).

Example  10

(R) -3 '-[5- (thiazol-5-yl) thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 5- (tri The title compound was prepared by a method analogous to that described in Example 5 from -n-butylstannyl) thiazole. The title compound (31 mg) was obtained as light solid, m / z 348 (MH ⁺ ).

Example  11

(R) -3 '-[5- (thiazol-4-yl) thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 4- (tri The title compound was prepared by a method analogous to that described in Example 5 from -n-butylstannyl) thiazole. The title compound (27 mg) was obtained as light solid, m / z 348 (MH ⁺ ).

Example  12

(R) -3 '-[4- (4- Pyridyl ) Thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(4-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and pyridine-4- The title compound was prepared from boronic acid by a method similar to that described in Example 1. The solid obtained from flash chromatography was additionally used as a eluent with a concentration gradient of 5 to 45% acetonitrile / water (each solvent containing 0.1% trifluoroacetic acid as a buffer) Phenomenex® Polar ) Purified by reverse phase HPLC of RP column. The residue was partitioned between saturated aqueous potassium carbonate and chloroform, then the chloroform layer was dried (magnesium sulfate), filtered and evaporated to give the title compound (74 mg) as m / z 342 (MH ⁺ ) as a light solid. .

Example  13

(R) -3 '-[4- (3- Pyridyl ) Thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(4-bromothiophen-2-yl) spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and pyridine-3- The title compound was prepared from boronic acid by a method similar to that described in Example 12. The title compound (73 mg) was obtained as light solid, m / z 342 (MH ⁺ ).

Example  14

(R) -3 '-[4- (2- Pyridyl ) Thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(4-bromothiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri The title compound was prepared by a method analogous to that described in Example 5 from -n-butylstannyl) pyridine. The solid obtained from flash chromatography was further purified by reverse phase HPLC of a polar reversed phase column using a gradient of 5 to 45% acetonitrile / water as eluent (each solvent containing 0.1% trifluoroacetic acid as buffer). . Product-containing fractions were evaporated. The residue was partitioned between saturated aqueous potassium carbonate and chloroform and then the chloroform layer was dried (magnesium sulfate), filtered and evaporated to give the title compound as m / z 342 (MH ⁺ ) as a light solid.

Example  15

(R) -3 '-[2- (4- Pyridyl ) Thiophen-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 4- Bromo -2- (4- Pyridyl Thiophene

2,4-dibromothiophene (2.97 g, 12.28 mmol), pyridine-4-boronic acid (1.50 g, 12.28 mmol) in ethanol / 1,2-dimethoxyethane (1: 4 v / v; 100 mL) , Potassium carbonate (5.52 g, 39.91 mmol) and tetrakis (triphenylphosphine) palladium (0) (426 mg, 0.38 mmol) were added to ethanol / 1,2-dimethoxyethane (1: 4 v / v; 100 mL) at reflux for 7 h. The solution was allowed to cool, then filtered and evaporated. The residue was purified by flash chromatography using a concentration gradient of ethyl acetate in hexanes to give a yellow solid, m / z 240,242 (MH ⁺ ) as a subtitle compound (1.52 g).

(b) (R) -3 '-(2- (4- Pyridyl Thiophen-4-yl) Spiro [One- Azabicyclo [2.2.2] octane -3, 5'- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 4-bromo-2 using 2 equivalents of copper (I) iodide The title compound was prepared by a similar method as described in Preparation 3 from-(4-pyridyl) thiophene. The title compound (1.70 g) was obtained as pale yellow solid, m / z 342 (MH ⁺ ).

Example  16

(R) -3 '-(2- (3- Pyridyl Thiophen-4-yl) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 4- Bromo -2- (3- Pyridyl Thiophene

The title compound was prepared by a method similar to that described in Example 15 for the preparation of 4-bromo-2- (4-pyridyl) thiophene from 2,4-dibromothiophene and pyridine-3-boronic acid. . A subtitle compound (2.30 g) was obtained as light solid, m / z 240,242 (MH ⁺ ).

(b) (R) -3 '-[2- (3- Pyridyl ) Thiophen-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3, 5'- Oxazolidine ] -2'-on

Prepared from (S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 4-bromo-2- (3-pyridyl) thiophene 3 The title compound was prepared by a method similar to that described in. The title compound (800 mg) was obtained as pale yellow solid, m / z 342 (MH ⁺ ).

Example  17

(R) -3 '-[2- (2- Pyridyl ) Thiophen-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 4- Bromo -2- (2- Pyridyl Thiophene

2,4-dibromothiophene (695 mg, 2.87 mmol), 2- (tri-n-butylstannyl) pyridine (830 mg, 1.92 mmol) and tetrakis (triphenylphosphine) palladium (0) (220 mg, 0.19 mmol) was refluxed at 120 ° C. in 3 mL of toluene overnight. After filtration of the solid residue, the reaction mixture was purified by flash chromatography using a gradient of ethyl acetate in hexanes to give a beige solid, m / z 240,242 (MH ⁺ ) as the title compound (340 mg).

(b) (R) -3 '-[2- (2- Pyridyl ) Thiophen-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3, 5'- Oxazolidine ] -2'-on

Prepared from (S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 4-bromo-2- (2-pyridyl) thiophene 3 The title compound was prepared by a method similar to that described in. As a pale yellow solid, the title compound (140 mg) was obtained m / z 342 (MH ⁺ ).

Example  18

(R) -3 '-(5- Phenylfuran -2 days) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

From (R) -3 '-(5-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and phenylboronic acid The title compound was prepared by a method similar to that described in Example 12. The title compound (49 mg) was obtained as pale yellow solid, m / z 325 (MH ⁺ ).

Example  19

(R) -3 '-[5- (4- Pyridyl ) Furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and pyridine-4- The title compound was prepared from boronic acid by a method similar to that described in Example 12. The title compound (701 mg) was obtained as light solid, m / z 326 (MH ⁺ ).

Example  20

(R) -3 '-[5- (3- Pyridyl ) Furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and pyridine-3- The title compound was prepared from boronic acid by a method similar to that described in Example 12. The title compound (206 mg) was obtained as light solid, m / z 326 (MH ⁺ ).

Example  21

(R) -3 '-[5- (2- Pyridyl ) Furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri The title compound was prepared by a method analogous to that described in Example 14 from -n-butylstannyl) pyridine. The title compound (356 mg) was obtained as off-white solid, m / z 326 (MH ⁺ ).

Example  22

(R) -3 '-[5- (thiazol-2-yl) furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri The title compound was prepared by a method analogous to that described in Example 14 from -n-butylstannyl) thiazole. The title compound (19 mg) was obtained as light solid, m / z 332 (MH ⁺ ).

Example  23

(R) -3 '-[5- (thiazol-5-yl) furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 5- (tri The title compound was prepared by a method analogous to that described in Example 14 from -n-butylstannyl) thiazole. The title compound (40 mg) was obtained as a light solid, m / z 332 (MH ⁺ ).

Example  24

(R) -3 '-[5- (thiazol-4-yl) furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(5-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 4- (tri The title compound was prepared by a method analogous to that described in Example 14 from -n-butylstannyl) thiazole. The title compound (81 mg) was obtained as light solid, m / z 332 (MH ⁺ ).

Example  25

(R) -3 '-[4- (4- Pyridyl ) Furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(4-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 4- (tri The title compound was prepared by a method analogous to that described in Example 14 from -n-butylstannyl) pyridine. The title compound (21 mg) was obtained as light solid, m / z 326 (MH ⁺ ).

Example  26

(R) -3 '-[4- (3- Pyridyl ) Furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3.5'- Oxazolidine ] -2'-on

(R) -3 '-(4-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and pyridine-3- The title compound was prepared from boronic acid by a method similar to that described in Example 12. The title compound (105 mg) was obtained as light solid, m / z 326 (MH ⁺ ).

Example  27

(R) -3 '-[4- (2- Pyridyl ) Furan-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(4-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri The title compound was prepared by a method analogous to that described in Example 14 from -n-butylstannyl) pyridine. The title compound (20 mg) was obtained as light solid, m / z 326 (MH ⁺ ).

Example  28

(R) -3 '-(4- (pyrazin-2-yl) furan-2-yl) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(R) -3 '-(4-bromofuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri The title compound was prepared by a method analogous to that described in Example 14 from -n-butylstannyl) pyrazine. The title compound (2 mg) was obtained as a light solid, m / z 327 (MH ⁺ ).

Example  29

(R) -3 '-(furan-3-yl) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

The title compound was prepared by a method similar to that described in Preparation 3 from (S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 3-bromofuran. Prepared. The title compound (445 mg) was obtained as pale yellow solid, m / z 249 (MH ⁺ ).

Example  30

(R) -3 '-[2- (4- Pyridyl ) Furan-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 4- Bromo -2- (4- Pyridyl ) -Furan

2,4-dibromo-5- (trimethylsilyl) furan (8.97 g), pyridine-4-boronic acid (1.85 g, 15.1 mmol), potassium carbonate (6.24 g, 45.2 mmol) and tetrakis (tri Phenylphosphine) palladium (0) (435 mg, 0.38 mmol) was heated at reflux for 6 h at 100 ° C. in ethanol / 1,2-dimethoxyethane (1: 4 v / v; 100 mL). The solution was allowed to cool, then filtered and evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in hexanes to give the title compound (1.45 g) as m / z 224,226 (MH ⁺ ) as a light brown solid.

(b) (R) -3 '-[2- (4- Pyridyl ) Furan-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5 '- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 4-bromo-2 using 4 equivalents of copper (I) iodide The title compound was prepared by a method analogous to that described in Preparation 3 from-(4-pyridyl) furan. The title compound (124 mg) was obtained as pale yellow solid, m / z 342 (MH ⁺ ).

Example  31

(R) -3 '-[2- (3- Pyridyl ) Furan-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 4- Bromo -2- (3- Pyridyl Furan

Subtitle compound by a method similar to that described for the preparation of 4-bromo-2- (4-pyridyl) -furan from 2,4-dibromo-5- (trimethylsilyl) furan and pyridine-3-boronic acid Was prepared. A subtitle compound (725 mg) was obtained as beige solid, m / z 224,226 (MH ⁺ ).

(b) (R) -3 '-[2- (3- Pyridyl ) Furan-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5 '- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 3-bromo-5- with 3 equivalents of copper (I) iodide The title compound was prepared by a method similar to that described in Preparation 3 from (3-pyridyl) -furan. The title compound (119 mg) was obtained as pale yellow solid, m / z 342 (MH ⁺ ).

Example  32

(R) -3 '-[2- (2- Pyridyl ) Furan-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 3- Bromo -5- (2- Pyridyl ) -3- ( Trimethylsilyl Furan

As described for the preparation of 4-bromo-2- (2-pyridyl) thiophene from 3,5-dibromo-2- (trimethylsilyl) furan and 2- (tri-n-butylstannyl) pyridine The title compound was prepared by a similar method. The title compound (4.96 g) was obtained as a light brown solid, m / z 296,298 (MH ⁺ ).

(b) 4- Bromo -2- (2- Pyridyl ) -Furan

Tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 25.1 mL, 25.11 mmol) was converted to 3-bromo-5- (2-pyridyl) -3- (trimethylsilyl in tetrahydrofuran (50 mL) ) Was added to a solution of furan (4.96 g, 16.74 mmol). The reaction mixture was heated at 70 ° C. (bath temperature) for 6 hours. The reaction mixture was evaporated and the residue was purified by flash chromatography using hexane as eluent to give the subtitle compound (3.02 g) as m / z 224,226 (MH ⁺ ) as a light brown solid.

(c) (R) -3 '-[2- (2- Pyridyl ) Furan-4-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5 '- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 3-bromo-5- with 2 equivalents of copper (I) iodide The title compound was prepared by a method similar to that described in Preparation 3 from (2-pyridyl) -furan. The title compound (90 mg) was obtained as pale yellow solid, m / z 342 (MH ⁺ ).

Example  33

3 '-[5- (4- Pyridyl ) Thiazol-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

3 '-(5-bromothiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 4- (tri-n-butyl The title compound was prepared by a method analogous to that described in Example 14 from stanyl) pyridine. The title compound (52 mg) was obtained as light solid, m / z 343 (MH ⁺ ).

Example  34

3 '-[5- (3- Pyridyl ) Thiazol-2-yl] Spiro [1-azabicyclo [2.2.2loctane-3,5'- Oxazolidine ] -2'-on

3 '-(5-bromothiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 3- (tri-n-butyl The title compound was prepared by a method analogous to that described in Example 14 from stanyl) pyridine. The title compound (87 mg) was obtained as light solid, m / z 343 (MH ⁺ ).

Example  35

3 '-[5- (2- Pyridyl ) Thiazol-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

3 '-(5-bromothiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 2- (tri-n-butyl The title compound was prepared by a method analogous to that described in Example 14 from stanyl) pyridine. The title compound (35 mg) was obtained as light solid, m / z 343 (MH ⁺ ).

Example  36 and 37

(R) -3 '-[5- (2- Pyridyl ) Thiazol-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'-oxazolidine] -2'-one ( Example  36) and (S) -3 '-[5- (2- Pyridyl ) Thiazol-2-yl] Spiro [One- Ah Xabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one ( Example  37)

Racemic 3 '-[5- (2-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one (implemented Example 35) was enantiomer by chiral supercritical fluid chromatography using isopropanol and supercritical carbon dioxide 1: 1 with isopropanol containing 0.5% dimethyl ethylamine as the eluent in a Chiral Pak AS-H column. The title compound was obtained as a colorless solid, m / z 343 (MH ⁺ ), respectively.

Example  38

(R) -3 '-[4- (4- Pyridyl ) Thiazol-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) (R) -3 '-(4- Bromothiazole -2 days) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one (1.00 g) stirred at room temperature in N, N-dimethyl formamide (15 mL) Sodium hydride (265 mg, 6.59 mmol) was added to the solution. The reaction mixture was then heated to 50 ° C. for 30 minutes. 2,4-Dibromothiazole (2.70 g, 10.98 mmol) was added to the reaction mixture and stirring at 50 ° C. was continued overnight. The mixture was allowed to cool and then quenched with saturated ammonium diluted with a large amount of chloroform. The organic layer was washed with saturated aqueous potassium carbonate, then dried (magnesium sulfate) and filtered and the solvent was evaporated. The residue was purified by flash chromatography using a concentration gradient of ammonia methanol in chloroform to give (R) -3 '-(4-bromotyazol-2-yl) spiro [1], m / z 344,346 (MH ⁺ ). Azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one with (R) -3 '-(4,5-dibro) being m / z 422, 424,426 (MH ⁺ ) A solid (369 mg) was obtained which was a 1: 1 mixture of mothiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one.

(b) (R) -3 '-[4- (4- Pyridyl ) Thiazol-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3, 5'- Oxazolidine ] -2'-on

(R) -3 '-(4-bromothiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and (R)- 4- (A mixture of 3 '-(4,5-dibromothiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one and 4- ( The title compound was prepared by a similar method as described in Example 14 from the reaction of tri-n-butylstannyl) pyridine. Reversed phase HPLC separation followed by conversion to the free base described in Example 14 gave the title compound m / z 343 (MH ⁺ ) and (R) -3 '-[4,5- which is m / z 420 (MH ⁺ ) Di (4-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2. 2] octane-3,5'-oxazolidine] -2'-one.

Example  39

(R) -3 '-[4- (3- Pyridyl ) Thiazol-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

The title compound was prepared by a method similar to that described in Example 38 using 3- (tri-n-butylstannyl) pyridine. Title compound as m / z 343 (MH ⁺ ) as a solid after reverse phase HPLC and conversion to free base and (R) -3 '-[4,5-di (3-pyridyl) as m / z 420 (MH ⁺ ) ) Thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one (61 mg) was obtained.

Example  40

(R) -3 '-[4- (2- Pyridyl ) Thiazol-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

The title compound was prepared by a method similar to that described in Example 38 using 2- (tri-n-butylstannyl) pyridine. Title compound with m / z 343 (MH ⁺ ) and (R) -3 '-(4,5-di (2-pyridyl) thiathia) with m / z 420 (MH ⁺ ) after reverse phase HPLC and conversion to free base Zol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one was obtained.

Example  41

(R) -3 '-[5- (4- Pyridyl ) -1,3,4- Thiadiazole -2 days] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 2- Bromo -5- (4- Pyridyl ) -1,3,4- Thiadiazole

2-amino-5- (4-pyridyl) -1,3,4-thiadiazole (2.0 g, 11.2 mmol) was suspended in 48% aqueous hydrobromic acid (5.6 mL) and stirred at 0 ° C. Bromine (5.06 mL, 98.8 mmol) was added dropwise to the mixture at 0 ° C. Water (15 mL) was added slowly followed by a slow addition of a solution of (2.8 mL) sodium nitrite (1.97 g, 28.6 mmol) in water. Stirring was continued for another 30 minutes at 0 ° C. Sodium hydroxide (10.0 g) in water (10 mL) was added slowly to the reaction mixture while maintaining the temperature below 20 ° C. The reaction mixture was then extracted with chloroform, then the chloroform solution was washed with water, dried (magnesium sulfate), filtered and the solvent was evaporated. The residue was purified by flash chromatography using a concentration gradient of ethyl acetate in hexanes to give the title compound (1.28 g) as m / z 242,244 (MH ⁺ ) as a brown solid.

(b) (R) -3 '[5- (4- Pyridyl ) 1,3,4- Thiadiazole -2 days] Spiro [One- Azabicyclo [2.2. 2] octane -3,5'- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 2-bromo-5 using 5 equivalents of copper (I) iodide The title compound was prepared by a similar method as described in Preparation 3 from-(4-pyridyl) -1,3,4-thiadiazole. The title compound was obtained as beige solid, m / z 344 (MH ⁺ ).

Example  42

(R) -3 '-(5- Phenyl -1,3,4- Thiadiazole -2 days) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 2- Bromo -5- Phenyl -1,3,4- Thiadiazole

Compounds were prepared from 2-amino-5-phenyl-1,3,4-thiadiazole by a method analogous to that described in Example 41 (a). The subtitle compound which is m / z 241,243 (MH ⁺ ) was obtained as a colorless solid.

(b) (R) -3 '-(5- Phenyl -1,3,4- Thiadiazole -2 days) Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 2-bromo-5 using 5 equivalents of copper (I) iodide Compounds were prepared by a method analogous to that described in Preparation 3 from -phenyl-1,3,4-thiadiazole. The title compound (180 mg) was obtained as a yellow solid, m / z 343 (MH ⁺ ).

Example  43

(R) -3 '-[5- (2- Pyrazolyl ) Thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(a) 2- Bromo -5- (2- Pyrazolyl Thiophene

2,5-dibromothiophene (5.0 mL, 10.3 g, 44.4 mmol), 2- (tri-n-butylstannyl) pyrazole (4.09 g, 11.0 mmol), tetrakis (triphenylphosphine) palladium ( 0) (0.67 g, 0.58 mmol) was heated to reflux in toluene (50 mL) for 6 h under argon atmosphere. The solution was evaporated and the residue was flash chromatographed with silica using 0-25% ethyl acetate / hexane as eluent. Evaporation of the product containing fractions gave the subtitle compound (771 mg) as m / z 241,243 (MH ⁺ ) as a solid.

(b) (R) -3 '-[5- (2- Pyrazolyl ) Thiophen-2-yl] Spiro [One- Azabicyclo [2.2.2] octane -3,5'- Oxazolidine ] -2'-on

(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one and 2-bromo-5 using 3.6 equivalents of copper (I) iodide Compounds were prepared by a method analogous to that described in Preparation 3 from-(2-pyrazolyl) thiophene. The title compound was obtained as light solid, m / z 343 (MH ⁺ ).

The present invention representatively includes, but is not limited to, the following compounds and their pharmaceutically acceptable salts which may be prepared by those skilled in the art using procedures and methods similar to those described herein.

(R) -3 '-(5-phenylthiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (4-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (3-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (2-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (thiophen-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (thiophen-3-yl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (furan-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3, 5'-oxazolidine] -2'- On;

(R) -3 '-[5- (furan-3-yl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (thiazol-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (thiazol-4-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (thiazol-5-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-(4-phenylthiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[4- (4-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[4- (3-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[4- (2-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[4- (thiophen-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[4- (thiophen-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3, 5'-oxazolidine] -2' -On;

(R) -3 '-[4- (furan-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[4- (furan-3-yl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[4- (thiazol-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[4- (thiazol-4-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[4- (thiazol-5-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-(2-phenylthiophen-4-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (4-pyridyl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (3-pyridyl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (2-pyridyl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (thiophen-2-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[2- (thiophen-3-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[2- (furan-2-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[2- (furan-3-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[2- (thiazol-2-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[2- (thiazol-4-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[2- (thiazol-5-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-(5-phenylfuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (4-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (3-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (2-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (thiophen-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (thiophen-3-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (furan-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (furan-3-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (thiazol-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (thiazol-4-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (thiazol-5-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-(4-phenylfuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[4- (4-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[4- (3-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[4- (2-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[4- (thiophen-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[4- (thiophen-3-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[4- (furan-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[4- (furan-3-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[4- (thiazol-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[4- (thiazol-4-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[4- (thiazol-5-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-(2-phenylfuran-4-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (4-pyridyl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (3-pyridyl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (2-pyridyl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (thiophen-2-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[2- (thiophen-3-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[2- (furan-2-yl) furan-4-yl] spiro (1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (furan-3-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (thiazol-2-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[2- (thiazol-4-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[2- (thiazol-5-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

3 '-[5- (4-pyridyl) -thiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

3 '-[5- (3-pyridyl) -thiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

3 '-[5- (2-pyridyl) -thiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (2-pyridyl) -thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(S) -3 '-[5- (2-pyridyl) -thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[4- (4-pyridyl) -thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[4- (3-pyridyl) -thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; And

(R) -3 '-[4- (2-pyridyl) -thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On.

The invention also representatively includes, but is not limited to, the following compounds and their pharmaceutically acceptable salts which may be prepared by those skilled in the art using processes and methods similar to those described herein.

(R) -3 '-{5- [3- (N, N-dimethylcarbamoyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'- Oxazolidin] -2'-one;

(R) -3 '-{5- [3- (N, N-diethylcarbamoyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5' -Oxazolidin] -2'-one;

(R) -3 '-{5- [3- (pyrrolidine-1-carbonyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'- Oxazolidin] -2'-one;

(R) -3 '-{5- [3- (piperidine-1-carbonyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'- Oxazolidin] -2'-one;

(R) -3 '-{5- [3- (morpholin-4-carbonyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one;

(R) -3 '-[5- (3-aminophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-{5- [3- (N, N-dimethylamino) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazoli Din] -2'-one;

(R) -3 '-{5- [3- (propionylamino) phenyl] thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2 '-On;

(R) -3 '-{5- [3- (butyrylamino) phenyl] thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2 '-On;

(R) -3'-5- [3- (benzoylamino) phenyl] thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2'- On;

(R) -3 '-{5- [3- (2-propoxy) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one;

(R) -3 '-[5- (3-trifluoromethoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2 '-On;

(R) -3 '-[5- (quinolin-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (quinolin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (quinolin-4-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (quinolin-5-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (quinolin-6-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (quinolin-7-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (quinolin-8-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (pyrimidin-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (pyrimidin-4-yl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (pyrimidin-5-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-(2-phenylthiazol-4-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (2-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (3-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (4-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-(2-phenylthiazol-5-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (2-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (3-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (4-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (2-pyridyl) -1,3,4-thiadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one;

(R) -3 '-[5- (3-pyridyl) -1,3,4-thiadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one;

(R) -3 '-(5-phenyl-1,3,4-oxadiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2 '-On;

(R) -3 '-(5-phenyloxazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (2-pyridyl) oxazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (3-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (4-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-(4-phenyloxazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[4- (2-pyridyl) oxazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[4- (3-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[4- (4-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-(2-phenyloxazol-4-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (2-pyridyl) oxazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (3-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (4-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-(2-phenyloxazol-5-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[2- (2-pyridyl) oxazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (3-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[2- (4-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (2-pyridyl) -1,3,4-oxadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one;

(R) -3 '-[5- (3-pyridyl) -1,3,4-oxadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one; And

(R) -3 '-[5- (4-pyridyl) -1,3,4-oxadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one.

Additionally, the present invention representatively includes, but is not limited to, the following compounds and their pharmaceutically acceptable salts which may be prepared by those skilled in the art using processes and methods similar to those described herein.

(R) -3 '-[5- (2-fluorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (3-fluorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (4-fluorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (2-chlorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (3-chlorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (4-chlorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ;

(R) -3 '-[5- (3,4-dichlorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (3-methylphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (4-methylphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one;

(R) -3 '-[5- (3-methoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (4-methoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (3-methoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (3-trifluoromethylphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (4-trifluoromethylphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (3-trifluoromethoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2 '-On;

(R) -3 '-[5- (4-trifluoromethoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2 '-On;

(R) -3 '-[5- (naphthalen-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On;

(R) -3 '-[5- (benzofuran-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On;

(R) -3 '-[5- (benzo [b] thiophen-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine ] -2'-one;

(R) -3 '-[5- (2-fluoropyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one;

(R) -3 '-[5- (2-chloropyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine]- 2'-one;

(R) -3 '-[5- (2-methoxypyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one;

(R) -3 '-[5- (2-aminopyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine]- 2'-one;

(R) -3 '-{5- [2- (N, N-dimethylamino) pyridin-3-yl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5 '-Oxazolidin] -2'-one;

(R) -3 '-[5- (5-chloropyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine]- 2'-one;

(R) -3 '-[5- (5-methoxypyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one;

(R) -3 '-[5- (5-aminopyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2 '-On; And

(R) -3 '-{5- [5- (N, N-dimethylamino) pyridin-3-yl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5 '-Oxazolidine] -2'-on.

Pharmacology

The tests presented below can be used to determine the pharmacological activity of the compounds of the invention.

Test A-α7 nAChR In subtype To affinity  Analysis

[ ¹²⁵ I] -α-Bungarodoxin (BTX) bound to the rat hippocampal membrane

The rat hippocampus was homogenized in a 20-fold volume of cold homogenization buffer (HB, concentration of component (mM): Tris (hydroxymethyl) aminomethane 50; MgCl ₂ 1; NaCl 120; KCl 5: pH 7.4). Homogenates were centrifuged at 1000 g for 5 minutes, supernatants were collected and pellets were re-extracted. The pooled supernatant was centrifuged at 12000 g for 20 minutes, washed and then resuspended in HB. Membrane (30-80 gag) [ ¹²⁵ I] α-BTX 5 nM, BSA (bovine serum albumin) 1 mg / mL, test drug and CaCl ₂ 2 mM or EGTA [ethylene glycol-bis (β-aminoethylether) Incubated with one of 0.5 mM and then filtered on Whatman glass fiber filter (thickness C) using a Brandel cell collector and washed four times. It is important to pretreat the filter for 3 hours with 1% BSA / 0.01% PEI (polyethylenimine) in water for a low filter blank (0.07% of total count per minute). Nonspecific binding was described as 100 μM (−)-nicotine and specific binding was typically 75%.

Test B-α4 nAChR  With a subtype To affinity  Analysis

[ ³ H]-(-)-nicotine bond.

Homogenized mouse brain (cortex and hippocampus) as in [ ¹²⁵ I] α-BTX binding assays using a procedure modified from Martino-Barrows and Kellar (Mol Pharm (1987) 31: 169-174) And centrifuged at 12,000 × g for 20 minutes and washed twice before resuspending in HB containing 100 μM of diisopropyl fluorophosphate. After 20 minutes at 4 ° C., the membrane (about 0.5 mg) was incubated with either [ ³ H]-(-)-nicotine 3 nM, test drug, atropine 1 μM and either CaCl ₂ 2 mM or EGTA 0.5 mM, followed by Filtration was performed on a Whatman glass fiber filter (thickness C, pretreated with 0.5% PEI for 1 hour) using a Dell cell collector. Nonspecific binding was described as 100 μM carbacol and specific binding was typically 84%.

Combined data analysis for exams A and B

IC ₅₀ values and pseudo-hill constants (nH) were calculated using the non-linear curve regression program ALLFIT (DeLean A, Munson PJ and Rodbard D (1977) Am. J. Physiol., 235: E97-E102) ]Reference). Using a non-linear regression program ENZFITTER (Leatherbarrow, RJ (1987)) to fit a saturation curve to a one site model [ ¹²⁵ I] -α-BTX and [ ³ H]-(-) KD values for the nicotine ligand were calculated to be 1.67 and 1.70, respectively. Ki value was estimated using the general Cheng-Prusoff formula of Equation I below.

Ki- [IC ₅₀ ] / ((2 + ([ligand] / [KD]) n) l / n-1)

In this case, n has a value of 1 when nH <1.5 and n has a value of 2 when nH ≥ 1.5. Samples were analyzed in triplicate, typically ± 5%. Ki values were determined using at least six drug concentrations. Compounds of the invention are compounds that have a binding affinity (Ki) of less than 1000 nM in Test A or Test B, indicating that they will have useful therapeutic activity.

The compounds of the present invention have the advantage of being less toxic, more potent, longer active, more extensive in activity, more potent, less adverse, easily absorbed or have other useful pharmacological properties.

Claims (29)

The compounds according to formula (I) and their pharmaceutically acceptable salts. <Formula I>

Wherein Q is a residue of formula <Formula II>

-A- is selected from -O-, -S- or -NR ¹ -or is a bond directly connecting Ar ¹ and Ar ² , Ar ^l is selected from Formula III or Formula IV, <Formula III>

<Formula IV>

B is O, S or NR ¹ , R ¹ in each occurrence is independently selected from hydrogen or R ³ , D is each independently selected from N or CR ² , provided that D is N in two cases or less, R ² independently in each occurrence is hydrogen, -R ³ , -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, halogen, -CN, -NO ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , -OR ⁸ , Q or a bond, provided that R ² is in one case Q, and in one case is a bond connecting Ar ^l to A or -A- If a bond, it is a bond to Ar ² , R ³ is selected from an unsubstituted straight, branched or cyclic C ₁ -C ₆ alkyl group, or up to 5 halogen atoms, and C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -CN, From straight, branched or cyclic C ₁ -C ₆ alkyl groups substituted with up to 2 substituents selected from -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ or -OR ⁸ Selected, R ⁴ in each occurrence is independently selected from hydrogen, R ⁹ , —NR ¹⁰ R ¹¹ or —OR ⁸ , R ⁵ in each occurrence is independently selected from hydrogen, R ⁹ or —NR ¹⁰ R ¹¹ , R ⁶ and R ⁷ are each independently selected from hydrogen, R ⁹ , —C (O) R ⁴ or —S (O) _n R ⁵ , or in any case of —NR ⁶ R ⁷ in combination ( CH ₂ ) _p G (CH ₂ ) _q , where G is O, S, NR ^8, or a bond, R ⁸ is selected from hydrogen or R ⁹ , R ⁹ is selected from an unsubstituted straight, branched or cyclic C ₁ -C ₆ alkyl group, or up to 5 halogen atoms, and C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -CN, -NR ¹⁰ R ¹¹ , -OR ^{12 It} is selected from a straight, branched or cyclic C ₁ -C ₆ alkyl group substituted with one or more substituents, R ¹⁰ and R ¹¹ are each independently selected from hydrogen, R ¹² , —C (O) R ¹² , —S (O) _n R ¹² , or in combination in any one case of —NR ¹⁰ R ¹¹ (CH ₂ ) _p J (CH ₂ ) _q , where J is O, S, NH, NR ^12, or a bond, Or R ¹² is selected from unsubstituted straight-chain, branched or cyclic C ₁ -C ₆ alkyl group, is selected from a straight, branched or cyclic C ₁ -C ₆ alkyl group substituted by no more than 5 halogen atoms, Ar ² is selected from an unsubstituted 5- or 6-membered aromatic or heteroaromatic ring containing 0-2 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, or 0-3 nitrogen Selected from 8-membered, 9-membered or 10-membered fused aromatic or heteroaromatic ring systems containing atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, or 0-2 nitrogen atoms, 0-1 Or a 5- or 6-membered aromatic or heteroaromatic ring containing 2 oxygen atoms and 0-1 sulfur atoms, or 0-3 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms It is selected from containing 8-membered, 9-membered or 10-membered fused aromatic or heteroaromatic ring system, wherein each said Ar ² moiety is R ³ , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl , Halogen, -CN, -NO ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , May have 1 to 3 substituents selected from -OR ⁸ , In each case n is 0, 1 or 2, In each case p is 2, 3 or 4, In each case q is 0, 1 or 2) The method of claim 1, Ar ¹ is selected from Formula III or IV, <Formula III>

<Formula IV>

B is O, S or NR ¹ , R ¹ in each occurrence is independently selected from hydrogen or R ³ , D is each independently selected from N or CR ² , provided that D is N in both cases, R ² is independently at each occurrence hydrogen, -R ³ , halogen, -CN, -NO ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , -OR ⁸ , Q Or a bond, provided that R ² is Q in one case, and in one case is a bond connecting Ar ^l to A, or -A- is a bond to Ar ² , R ³ is an unsubstituted straight, branched or cyclic C ₁ -C ₆ alkyl group or up to 5 halogen atoms, and —CN, —C (O) R ⁴ , —S (O) _n R ⁵ , — A linear, branched or cyclic C ₁ -C ₆ alkyl group substituted with up to 2 substituents selected from NR ⁶ R ⁷ or -OR ⁸ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from hydrogen or R ⁹ , R ⁹ is selected from unsubstituted straight chain, branched or cyclic C ₁ -C ₆ alkyl group, or up to 5 halogen atoms, and up to 1 substituent selected from -CN, -NR ¹⁰ R ¹¹ , -OR ¹² Selected from substituted straight chain, branched or cyclic C ₁ -C ₆ alkyl groups, R ¹⁰ and R ¹¹ in each case are hydrogen, R ¹² is selected from an unsubstituted straight chain, branched or cyclic C ₁ -C ₆ alkyl group, or is selected from a straight chain, branched or cyclic C ₁ -C ₆ alkyl group substituted with up to 5 halogen atoms; , -A- is selected from -O-, -S- or -NR ¹ -or is a bond directly connecting Ar ¹ and Ar ² , Ar ² is unsubstituted phenyl; 2-pyridyl, 3-pyridyl or 4-pyridyl; 2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl; 2-pyrazinyl or 3-pyrazinyl; 2-furyl or 3-furyl; 2-thiophenyl or 3-thiophenyl; 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl; 2-quinazolyl, 4-quinazolyl or 5-quinazolyl; 2-oxazolyl, 4-oxazolyl or 5-oxazolyl; 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; 1-naphthyl or 2-naphthyl; 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl; 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl or 8-isoquinolyl; 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl or 7-benzofuranyl; 2-benzo [b] thiophenyl, 3-benzo [b] thiophenyl, 4-benzo [b] thiophenyl, 5-benzo [b] thiophenyl, 6-benzo [b] thiophenyl or 7-benzo [b ] Thiophenyl; 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl; 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl or 7-benzoxazolyl; 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl or 7-benzthiazolyl, or R ³ , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkoxy Any of the above substituted with one to three substituents selected from nil, halogen, -CN, -N0 ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ , -OR ⁸ Selected from an Ar ² residue, In each case n is 0, 1 or 2; 2. The compound of claim 1 wherein R ² is Q in one case, in one case a bond connecting Ar ¹ to A, and in other cases hydrogen. The compound of claim 1, wherein Q and -A-Ar ² are in a 1,3 relationship to each other at Ar ¹ . The compound of claim 1, wherein -A- is a bond directly connecting Ar ¹ and Ar ² . The compound of claim 1, wherein Ar ¹ is a residue of Formula III. The compound of claim 1, wherein Ar ¹ is selected from a furan ring or a thiophene ring. The compound of claim 1, wherein Ar ¹ is a residue of Formula III and B is selected from O or S. 5. The compound of claim 1, wherein Ar ¹ is a residue of Formula III and B is S. 3. The compound of claim 1, wherein Ar ¹ is a residue of Formula III and D is CR ^2. Wherein R ² is Q in one case, and in one case is a bond connecting Ar ¹ to A, and in other cases hydrogen. The method of claim 1, R ³ is methyl, ethyl, Linear, cyclic or branched propyl, butyl, pentyl or hexyl, Ethenyl, 1-propenyl, 2-propenyl or 3-propenyl, Linear, branched or cyclic butenyl, pentenyl or hexenyl, Ethynyl or propynyl, Chloro, bromo, fluoro, iodo, -CN, -N0 ₂ , -C (O) R ⁴ , -S (O) _n R ⁵ , -NR ⁶ R ⁷ or -OR ⁸ , R ⁴ is independently at each occurrence hydrogen, R ⁹ , —NR ¹⁰ R ¹¹ , —OR ⁸ , trifluoromethyl, trifluoroethyl, methoxymethyl, trifluoromethoxymethyl, methoxyethyl or trifluoromethoxy Selected from ethyl, R ⁵ in each occurrence is independently selected from hydrogen, R ⁹ or —NR ¹⁰ R ¹¹ , R ⁶ and R ⁷ are each independently selected from hydrogen, R ⁹ , —C (O) R ⁴ or —S (O) _n R ⁵ , or in any case of —NR ⁶ R ⁷ in combination (CH ₂ ) _p G (CH ₂ ) _q , where G is O, S, NR ⁸ or a bond, R ⁸ is selected from hydrogen or R ⁹ , R ⁹ is methyl, ethyl, Linear, cyclic or branched propyl, butyl, pentyl or hexyl, Ethenyl, 1-propenyl, 2-propenyl or 3-propenyl, Linear, branched or cyclic butenyl, pentenyl or hexenyl, Selected from ethynyl or propynyl, wherein any of the R ⁹ moieties is chloro, bromo, fluoro, iodo atoms up to 5 atoms, and one substituent selected from -CN, -NR ¹⁰ R ¹¹ , -OR ¹² May contain R ¹⁰ and R ^ll are each independently selected from hydrogen, R ¹² , —C (O) R ¹² , —S (O) _n R ¹² , or in combination in any one case of —NR ⁶ R ⁷ (CH ₂ ) _p J (CH ₂ ) _q , where J is O, S, NR ¹² or a bond, R ¹² is methyl, ethyl, Linear, cyclic or branched propyl, butyl, pentyl or hexyl, Ethenyl, 1-propenyl, 2-propenyl or 3-propenyl, Linear, branched or cyclic butenyl, pentenyl or hexenyl, Selected from ethynyl or propynyl, wherein any of the R ¹² residues may contain up to 5 chloro, bromo, fluoro, iodo atoms, Ar ² is unsubstituted phenyl; 2-pyridyl, 3-pyridyl or 4-pyridyl; 2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl; 2-pyrazinyl or 3-pyrazinyl; 2-furyl or 3-furyl; 2-thiophenyl or 3-thiophenyl; 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl; 2-quinazolyl, 4-quinazolyl or 5-quinazolyl; 2-oxazolyl, 4-oxazolyl or 5-oxazolyl; 2-imidazolyl, 4-imidazolyl or 5-imidazolyl; 1-naphthyl or 2-naphthyl; 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl; 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl or 8-isoquinolyl; 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl or 7-benzofuranyl; 2-benzo [b] thiophenyl, 3-benzo [b] thiophenyl, 4-benzo [b] thiophenyl, 5-benzo [b] thiophenyl, 6-benzo [b] thiophenyl or 7-benzo [b ] Thiophenyl; 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl; 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl or 7-benzoxazolyl; 2-benzthiazolyl, 4-benzthiazolyl, 5-benzthiazolyl, 6-benzthiazolyl or 7-benzthiazolyl; Or any of the above Ar ² residues substituted with 1, 2 or 3 R ³ substituents. The method of claim 1, (R) -3 '-(5-phenylthiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[5- (4-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (3-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (2-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (thiophen-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (thiophen-3-yl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (furan-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3, 5'-oxazolidine] -2'- On; (R) -3 '-[5- (furan-3-yl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (thiazol-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (thiazol-4-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (thiazol-5-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-(4-phenylthiophen-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[4- (4-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[4- (3-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[4- (2-pyridyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[4- (thiophen-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[4- (thiophen-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3, 5'-oxazolidine] -2' -On; (R) -3 '-[4- (furan-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[4- (furan-3-yl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[4- (thiazol-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[4- (thiazol-4-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[4- (thiazol-5-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-(2-phenylthiophen-4-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (4-pyridyl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (3-pyridyl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (2-pyridyl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (thiophen-2-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[2- (thiophen-3-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[2- (furan-2-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[2- (furan-3-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[2- (thiazol-2-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[2- (thiazol-4-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[2- (thiazol-5-yl) thiophen-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-(5-phenylfuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[5- (4-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[5- (3-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[5- (2-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[5- (thiophen-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (thiophen-3-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (furan-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (furan-3-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (thiazol-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (thiazol-4-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (thiazol-5-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-(4-phenylfuran-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[4- (4-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[4- (3-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[4- (2-pyridyl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[4- (thiophen-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[4- (thiophen-3-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[4- (furan-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[4- (furan-3-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[4- (thiazol-2-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[4- (thiazol-4-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[4- (thiazol-5-yl) furan-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-(2-phenylfuran-4-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (4-pyridyl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (3-pyridyl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (2-pyridyl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (thiophen-2-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[2- (thiophen-3-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[2- (furan-2-yl) furan-4-yl] spiro (1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (furan-3-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (thiazol-2-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[2- (thiazol-4-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; or (R) -3 '-[2- (thiazol-5-yl) furan-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; Or pharmaceutically acceptable salts thereof Compound selected from. The method of claim 1, (R) -3 '-{5- [3- (N, N-dimethylcarbamoyl) phenyl] thiophen-2-yl} spiro [l-azabicyclo [2.2.2] octane-3,5'- Oxazolidin] -2'-one; (R) -3 '-{5- [3- (N, N-diethylcarbamoyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5' -Oxazolidin] -2'-one; (R) -3 '-{5- [3- (pyrrolidine-1-carbonyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'- Oxazolidin] -2'-one; (R) -3 '-{5- [3- (piperidine-1-carbonyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'- Oxazolidin] -2'-one; (R) -3 '-{5- [3- (morpholin-4-carbonyl) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one; (R) -3 '-[5- (3-aminophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-{5- [3- (N, N-dimethylamino) phenyl] thiophen-2-yl} spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazoli Din] -2'-one; (R) -3 '-{5- [3- (propionylamino) phenyl] thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2 '-On; (R) -3 '-{5- [3- (butyrylamino) phenyl] thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2 '-On; (R) -3 '-{5- [3- (benzoylamino) phenyl] thiophen-2-yl} spiro [l-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2' -On; (R) -3 '-{5- [3- (2-propoxy) phenyl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one; (R) -3 '-[5- (3-trifluoromethoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2 '-On; (R) -3 '-[5- (quinolin-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (quinolin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (quinolin-4-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (quinolin-5-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (quinolin-6-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (quinolin-7-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (quinolin-8-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (pyrimidin-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (pyrimidin-4-yl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (pyrimidin-5-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-(2-phenylthiazol-4-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (2-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (3-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (4-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-(2-phenylthiazol-5-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (2-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (3-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (4-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (2-pyridyl) -1,3,4-thiadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one; (R) -3 '-[5- (3-pyridyl) -1,3,4-thiadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one; (R) -3 '-(5-phenyl-1,3,4-oxadiazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2 '-On; (R) -3 '-(5-phenyloxazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[5- (2-pyridyl) oxazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (3-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (4-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-(4-phenyloxazol-2-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[4- (2-pyridyl) oxazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[4- (3-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[4- (4-pyridyl) thiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-(2-phenyloxazol-4-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (2-pyridyl) oxazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (3-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (4-pyridyl) thiazol-4-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-(2-phenyloxazol-5-yl) spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[2- (2-pyridyl) oxazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (3-pyridyl) thiazol-5-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[2- (4-pyridyl) thiazol-5-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (2-pyridyl) -1,3,4-oxadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one; (R) -3 '-[5- (3-pyridyl) -1,3,4-oxadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidin] -2'-one; And (R) -3 '-[5- (4-pyridyl) -1,3,4-oxadiazol-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxa Zolidine] -2'-on Compound selected from. The method of claim 1, (R) -3 '-[5- (2-fluorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (3-fluorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (4-fluorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (2-chlorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (3-chlorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (4-chlorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one ; (R) -3 '-[5- (3,4-dichlorophenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (3-methylphenyl) thiophen-2-yl] spiro [l-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[5- (4-methylphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin] -2'-one; (R) -3 '-[5- (3-methoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (4-methoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (3-methoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (3-trifluoromethylphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (4-trifluoromethylphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (3-trifluoromethoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2 '-On; (R) -3 '-[5- (4-trifluoromethoxyphenyl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2 '-On; (R) -3 '-[5- (naphthalen-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'- On; (R) -3 '-[5- (benzofuran-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2' -On; (R) -3 '-[5- (benzo [b] thiophen-2-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2'-one; (R) -3 '-[5- (2-fluoropyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one; (R) -3 '-[5- (2-chloropyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2 '-On; (R) -3 '-[5- (2-methoxypyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one; (R) -3 '-[5- (2-aminopyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine]- 2'-one; (R) -3 '-{5- [2- (N, N-dimethylamino) pyridin-3-yl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5 '-Oxazolidin] -2'-one; (R) -3 '-[5- (5-chloropyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2 '-On; (R) -3 '-[5- (5-methoxypyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidine] -2'-one; (R) -3 '-[5- (5-aminopyridin-3-yl) thiophen-2-yl] spiro [1-azabicyclo [2.2.2] octane-3,5'oxazolidine] -2 '-On; And (R) -3 '-{5- [5- (N, N-dimethylamino) pyridin-3-yl] thiophen-2-yl} spiro [1-azabicyclo [2.2.2] octane-3,5 '-Oxazolidine] -2'-on Compound selected from. The compound of claim 1, wherein at least one of the elements of the compound is a radioisotope of the element. The compound of claim 15, wherein the radioisotope is tritium. to bind to the α7 nicotinic acetylcholine receptor and modulate its activity by their agonist action, partial agonist action or antagonism, comprising measuring the substitution of the compound according to claim 15 from the α7 nicotinic acetylcholine receptor Method of Discovery of New Pharmaceutical Compounds. A method of treating or preventing a disease or condition in humans in which the activation of the a7 nicotinic receptor is advantageous, comprising administering a therapeutically effective amount of the compound of claim 1. 19. The method of claim 18, wherein the disease or condition of the human is selected from a nervous system disorder, a psychotic disorder or an impairment of intellectual disability. 19. The method of claim 18, wherein the human disease or condition is Alzheimer's disease, learning deficiency, cognitive deficiency, attention deficit, memory loss, attention deficit hyperactivity disorder, Parkinson's disease, Huntington's disease, Tourette syndrome, loss of cholinergic synapse. Neurodegenerative disorders, anxiety, schizophrenia or manic depression. A method of treatment for jet lag, induction of smoking cessation, nicotine intoxication, cravings, pain and ulcerative colitis, comprising administering a therapeutically effective amount of a compound according to claim 1. A pharmaceutical composition comprising a compound according to claim 1, an enantiomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. Treating or treating a condition or disorder in said mammal comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition according to claim 22 to a mammal in need thereof for the treatment or prevention of a disorder or condition resulting from a disorder of nicotinic acetylcholine receptor neurotransmission. How to prevent. A method of treating or preventing a disease or condition in humans in which the activation of the a7 nicotinic receptor is advantageous, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 22. The method of claim 24, wherein the disease or condition of the human is selected from a nervous system disorder, a psychotic disorder or an impairment of intellectual disability. The method of claim 25, wherein the human disease or condition is Alzheimer's disease, learning deficiency, cognitive deficiency, attention deficit, memory loss, attention deficit hyperactivity disorder, anxiety, schizophrenia, manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome, A method selected from nicotine poisoning, craving, pain and ulcerative colitis, including neurodegenerative disorders with loss of cholinergic synapses, jet lag, smoking cessation, exposure to products containing nicotine.  diseases or conditions in which the activation of the α7 nicotinic receptor is favorable, neurological disorders, psychosis disorders, impaired intelligence disorders, Alzheimer's disease, learning deficits, cognitive deficits, attention deficit, memory loss, attention deficit hyperactivity disorder, anxiety, schizophrenia, mood swings, Use of a compound according to claim 1 in the manufacture of a medicament for the treatment or prevention of Parkinson's disease, Huntington's disease, Tourette syndrome or neurodegenerative disorders with loss of cholinergic synapses. Use of a compound according to claim 1 in the manufacture of a drug for jet lag, pain or ulcerative colitis. Use of a compound according to claim 1 in the manufacture of a medicament for facilitating the treatment of nicotine poisoning or craving, including from smoking cessation or exposure to nicotine containing products.